Breast cancer has been a principal focus of research at the UT Health Science Center in San Antonio for more than 20 years. The concept of translational research, bringing new laboratory findings quickly to clinical application to improve the treatment, quality of life, and survival of breast cancer patients, has been an integral part of this research since the beginning. Under the first years of our SPORE, the same extensive breast tumor bank and database with long-term clinical follow-up which makes this rapid translation possible has become a national resource, while basic cell and molecular biology research with the potential for early clinical implications is also ongoing. In this SPORE renewal application, we propose the further development of our translational breast cancer research emphasis, in several directions. (1) Our basic studies of acquired tamoxifen resistance will test new mechanistic hypotheses, and strategies for overcoming this resistance in patients will be explored. (2) Our laboratory discoveries on the association of heat shock proteins with drug resistance will be translated into preclinical and clinical studies of methods of reversing this resistance. (3) Our ongoing study of marker antigens such as oncogene proteins, invasion enzymes, and proliferation markers in evolutionary stages of premalignant breast lesions will provide potential surrogate endpoints to be evaluated in a tamoxifen chemoprevention trial. (4) Having demonstrated both the clonal nature of premalignant lesions and their clonal progression to invasive breast cancer, we will seek genetic markers of risk to guide preventive treatment choices. (5) Our findings on tumor suppressor genes, and particularly on a newly discovered set of Rb- associated proteins, will be applied to define the role of a number of suppressor genes in clinical breast cancer, their use as biomarkers of prognosis and risk, and the possibilities of therapeutic reversal of their functional loss by adenovirus vectors carrying the normal genes. (6) Our long experience with both tumor and data collection in the San Antonio Breast Tumor Bank has been used to develop a SPORE National Breast Cancer Tissue Resource, which will continue to provide investigators all over the country with access to breast cancer specimens and associated clinical data. (7) Our Familial Breast Cancer Resource has already accrued over 200 breast cancer families, and will continue to identify families and collect blood samples for molecular genetic investigation, focusing in particular on the large and highly localized Hispanic families in our region. (8) At least four developmental studies which could lead to early clinical application will be undertaken at any one time; current examples include preclinical study and a phase I clinical trial of IGF binding protein 1 as targeted therapy, development of comparative genomic hybridization (CGH) for paraffin-embedded archival breast tissue samples to screen cancers and premalignant lesions for genetic abnormalities, chemical modification of the drug camptothecin to stabilize the bioactive lactone form and enhance bioavailability, and development of a culturally sensitive decision instrument to investigate ways of overcoming the resistance of many Hispanic women to mammography screening. (9) Two career development awards will be made each year for research work on specifically translational projects in breast cancer, to encourage development of focused research careers in this area.